Thrombophilia in young patients with cryptogenic stroke and patent foramen ovale (PFO)

Leeuw

2010

J Thromb Thrombolysis

To analyze risk factors for ischemic stroke and transient ischemic attack (TIA) in young adults under the age of 50. To make recommendations for additional research and practical consequences. From 97 patients with ischemic stroke or TIA under the age of 50, classical cardiovascular risk factors, coagulation disorders, history of migraine, use of oral contraceptives, cardiac abnormalities on ECG and echocardiography, and the results of duplex ultrasound were retrospectively analyzed. Literature was reviewed and compared to the results. 56.4% of the patients had hypertension, 12.1% increased total cholesterol, 20% hypertriglyceridemia, 31.5% an increased LDL-level, 32.6% a decreased HDL-level and 7.2% a disturbed glucose tolerance. Thrombophilia investigation was abnormal in 21 patients and auto-immune serology was abnormal in 15 patients. Ten of these patients were already known with a systemic disease associated with an increased risk for ischemic stroke (i.e. systemic lupus erythematosus). The ECG was abnormal in 16.7% of the cases, the echocardiography in 12.1% and duplex ultrasound of the carotid arteries was in 31.8% of the cases abnormal. Conventional cardiovascular risk factors are not only important in patients over the age of 50 with ischemic stroke or TIA, but also in this younger population under the age of 50. Thrombophilia investigation and/ or autoimmune serology should be restricted to patients without conventional cardiovascular risk factors and a history or other clinical symptoms associated with hypercoagulability and/ or autoimmune diseases.

Section: Discussionmentioning

confidence: 99%

Risk factors for ischemic stroke and transient ischemic attack in patients under age 50

Leeuw

2010

J Thromb Thrombolysis

“…These studies also produced conflicting results, with some studies suggesting an association between PTM or FVL and PFO, 24,[41][42][43] and others finding no relation. 21,[37][38][39][40] None of the studies that examined PC, PS, or AT found any association of these deficiencies with PFO and stroke. [37][38][39][40]42 No study has evaluated the utility of warfarin vs antiplatelets for patients with PFO and thrombophilia.…”

Section: Inherited Thrombophilia and Patent Foramen Ovalementioning

confidence: 98%

“…21,[37][38][39][40] None of the studies that examined PC, PS, or AT found any association of these deficiencies with PFO and stroke. [37][38][39][40]42 No study has evaluated the utility of warfarin vs antiplatelets for patients with PFO and thrombophilia. One small study of 72 patients referred for PFO closure found no difference in recurrent stroke at 6 months in patients with or without thrombophilia.…”

Section: Inherited Thrombophilia and Patent Foramen Ovalementioning

confidence: 98%

“…Without limitation to the number of subjects, we identified 9 case-control studies examining the relationship of the inherited thrombophilias, patent foramen ovale (PFO), and stroke 21,24,[37][38][39][40][41][42][43] (Table 3). Sastry et al 9 collected data on both PFO and thrombophilia in ischemic stroke but did not evaluate them in relation to each other.…”

Section: Inherited Thrombophilia and Patent Foramen Ovalementioning

confidence: 99%

See 1 more Smart Citation

Testing for Inherited Thrombophilias in Arterial Stroke

Morris¹,

Singh²,

Fisher³

2010

Stroke

109

Background and Purpose-Despite a paucity of evidence supporting a true association of ischemic stroke and the inherited thrombophilias, it is common practice for many neurologists to order these tests as part of the work-up of ischemic stroke, especially in young patients. Treatment with oral anticoagulation is often used in patients with positive results for the inherited thrombophilias. Methods-We reviewed the literature focusing on case-control studies of the 5 most commonly inherited disorders of coagulation: protein C deficiency, protein S deficiency, antithrombin deficiency, and the factor V Leiden and prothrombin gene mutations in patients with stroke. We also analyzed the available data on stroke patients with inherited thrombophilia and patent foramen ovale. Results-Multiple case-control studies have not convincingly shown an association of the inherited thrombophilias with ischemic stroke, even in young patients and patients with patent foramen ovale. Conclusion-If there is an association between the inherited thrombophilias and arterial stroke, then it is a weak one, likely enhanced by other prothrombotic risk factors. The consequences of ordering these tests and attributing causality to an arterial event can result in significant costs to the health care system and pose a potential risk to patients, because this may lead to inappropriate use of long-term oral anticoagulants, exposing patients to harm without a clearly defined benefit. (Stroke. 2010;41:2985-2990.)Key Words: blood coagulation disorders Ⅲ inherited Ⅲ foramen ovale Ⅲ patent Ⅲ stroke Ⅲ thrombophilia P atients with inherited thrombophilias are known to be at increased risk for venous thromboembolism (VTE), but a causal relationship with arterial thrombosis has not been clearly established. The data supporting thrombophilias as a cause of arterial stroke are limited predominantly to case reports and uncontrolled studies with mixed results from meta-analyses. Case-control studies do not consistently support an association of these disorders with stroke. Despite many authorities stating that these tests should not be ordered routinely in the work-up of ischemic stroke, 1-3 many books and articles continue to perpetuate the need to order these tests as part of the stroke work-up, especially in the young. 4,5 We review the current literature on the inherited thrombophilias in ischemic arterial stroke, present a cost and risk-benefit analysis, and suggest when testing should be considered. Materials and MethodsThe PubMed and Ovid Medline databases from 1950 to present were searched using "stroke" combined with the following key words: "thrombophilia," "protein C deficiency," "protein S deficiency," "antithrombin III deficiency," "factor V Leiden," and "prothrombin gene mutation." Additional searches with these terms and "patent foramen ovale" were also performed. Limits of human and English language were imposed, although if abstracts could be obtained in English they were included. All results were searched for relevant data and divided into ca...

“…Trial organizers risk enrolling patients who do not satisfy the classification criteria for the syndrome if they randomize patients after they initially test positive. This possibility is emphasized by a recent study 95 looking at young adults who had sustained a stroke and were noted to have a patent foramen ovale. Twelve had elevated titers (Ͼ 99th centile of normals) of IgG and IgM anti-␤ 2 GPI antibodies on initial testing, and yet on repeat testing at 12 weeks, only 1 of the 12 remained positive.…”

Section: Distinct Risk Profile Of Persistent Versus Transient Antibodmentioning

confidence: 99%

How we diagnose the antiphospholipid syndrome

Giannakopoulos

Passam

Ioannou

et al. 2009

Blood

163

IntroductionThe antiphospholipid syndrome (APS) is an important cause of acquired thrombophilia and recurrent miscarriages. This narrativestyle review discusses the key laboratory and clinical aspects of APS. Particular focus is given to antibodies against beta 2-glycoprotein I (␤ 2 GPI), in view of their recent inclusion in the APS laboratory classification criteria 1 (Figure 1). The evidence for assessing antiprothrombin and antiphosphatidylethanolamine antibodies to diagnose APS is also examined.The utility of the ␤ 2 GPI enzyme-linked immunosorbent assay (ELISA), when used in conjunction with the cardiolipin (CL) ELISA and the lupus anticoagulant (LA) assays, in risk-stratifying APS patients is explored. Work undertaken by many groups over the years, ours included, in delineating the key characteristics of anti-␤ 2 GPI antibodies that associate with APS is presented.Miscarriages are a major feature of APS. The relative importance of the LA assays, the CL-ELISA, and the ␤ 2 GPI-ELISA in diagnosing APS in the context of early and late gestation miscarriages is assessed. The value of recent epidemiologic and basic science insights in refining our understanding of obstetric APS pathophysiology is examined, particularly with regards to considering the possibility that distinct mechanisms may be responsible for early and late miscarriages. The clinical implications arising from these observations are discussed. Clarification of the nomenclatureAntiphospholipid antibodies is a term applied to antibodies detected traditionally by 2 types of assays, the CL-ELISA, which stems from the earlier work of Harris et al, 2 and the LA assays. 3 The first report of a cofactor requirement for antibodies to bind cardiolipin (an anionic phospholipid) from patients with APS was by McNeil et al in 1989. 4 This was subsequently confirmed by Galli et al 5 and Matsuura et al 6 in 1990. Purification and sequencing of the cofactor as ␤ 2 GPI was reported by McNeil et al in 1990. 7 It was noted that anionic phospholipid is not an absolute requirement for antibodies to bind ␤ 2 GPI, 8 negating the notion that ␤ 2 GPI is a "cofactor" for antibody binding. Antibodies from these patients can bind to ␤ 2 GPI immobilized on an irradiated plate in the absence of anionic phospholipids. 9 A negatively charged surface serves a 2-fold role. It enables ␤ 2 GPI clustering, allowing divalent binding by the low affinity antibodies. 10,11 It also enables the ␤ 2 GPI molecule to undergo a conformational change, 9 exposing a cryptic epitope on the first domain. 12 Positivity on the CL-ELISA is not directed against ␤ 2 GPI in the context of a number of infections. 13 However, this is not true for all types of infections, as elevated anti-␤ 2 GPI antibodies in patients with leishmaniasis, leptospirosis, 14 and leprosy 15 have been noted. A key distinguishing feature between anti-␤ 2 GPI antibodies occurring in the context of leprosy and those that strongly associate with thrombosis is that in the former instance they are directed against an epitope on dom...